Effectiveness and Safety of Intranasal Glucagon for Treatment of Hypoglycemia in Adults

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The primary objective of this study is to assess the effectiveness and safety of 3 mg glucagon (AMG504-1) administered as a puff into the nose compared with commercially-available glucagon given by injection.

Condition or disease

Intervention/treatment

Phase

Diabetes Mellitus, Type 1Diabetes Mellitus, Type 2

Drug: Intranasal GlucagonDrug: Intramuscular Glucagon

Phase 3

Detailed Description:

Glucagon, the treatment of choice for severe hypoglycemia outside of the hospital setting, is currently available only as a powder that must be mixed with a diluent immediately prior to administration by injection. Although this is a very simple procedure for insulin-using individuals, subjects experiencing severe hypoglycemia cannot inject themselves with glucagon because of the disabling effects of severe neuroglycopenia. For any non-medical person who is confronted with an emergency situation in which a patient with diabetes is in a hypoglycemic coma or suffering hypoglycemia-related convulsions, reconstitution and injection of the current injectable glucagon is a complex and daunting procedure.

When used at the recommended dose of 1 mg by injection, glucagon often causes a substantial, although transient, hyperglycemia that is often accompanied by nausea and vomiting. The data generated to date with AMG504-1 suggest the resulting glucagon pharmacokinetics (PK), although less than that observed with injected glucagon, results in a therapeutic blood glucose increment with a very low incidence of gastrointestinal adverse effects.

The procedure to evaluate the efficacy of AMG504-1 consists essentially of inducing hypoglycemia by an intravenous (IV) infusion of regular insulin diluted in normal saline. The insulin infusion will be used to decrease the glucose to a target <50 mg/dL. The insulin infusion will be stopped once the plasma glucose is <60 mg/dL. Five minutes after stopping the insulin infusion, participants will be treated with either a 3 mg glucagon dose intranasally or 1 mg of glucagon administered by intramuscular (IM) injection in the deltoid muscle of the non-dominant arm. During the 5-minute period after the insulin infusion has stopped, the glucose level is expected to continue to decrease an additional 15-20 mg/dL.

It is believed that a nadir of <50 mg/dL will be low enough to generate clinical symptoms in most participants yet high enough to avoid impairment of consciousness. Blood glucose levels and adverse events will be carefully monitored for 90 minutes post-dosing. After a wash-out period of 7 days or more, participants will return to the clinic and the procedure repeated with each participant crossed over to the other treatment. As such, each participant will undergo two episodes of insulin-induced hypoglycemia in random order and receive AMG504-1 during one episode and commercially available glucagon (GlucaGen, Novo Nordisk) by IM injection during the other episode.

At one visit, a glucagon dose of 3 mg (equivalent to 30 mg of AMG 504-1 dry powder) will be administered in a nostril with a prefilled delivery device that delivers a single dose upon activation.

Drug: Intranasal Glucagon

Other Name: AMG504-1

Active Comparator: Intramuscular Glucagon

At a separate visit, 1 mg of commercially available recombinant human glucagon United States Pharmacopeia (USP) will be constituted in the provided prefilled disposable syringe containing 1 mL of diluting solution for injection into the deltoid muscle of the non-dominant arm.

Increase in Plasma Glucose Level to >=70mg/dL or an Increase of >=20mg/dL [ Time Frame: within 30 minutes after receiving glucagon ]

Increase in blood glucose to >=70 mg/dL or an increase of >=20 mg/dL within 30 minutes after receiving glucagon, without receiving additional actions to increase the blood glucose level such as oral or intravenous glucose or additional glucagon.

Recovery From Symptoms of Hypoglycemia [ Time Frame: plasma glucose <75 mg/dl to 60 minutes following administration of glucagon ]

Recovery from clinical symptoms of hypoglycemia if present as documented using the hypoglycemia symptoms questionnaire which is completed when the plasma glucose reaches <75 mg/dL and at 15, 30, 45 and 60 minutes following administration of glucagon.

Time From Glucagon Administration to Return of Plasma Glucose to >/=70 mg/dL [ Time Frame: 0 to 90 minutes following glucagon administration ]

Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUC0-t) of Glucagon [ Time Frame: 0 to 90 minutes following glucagon administration ]

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Ages Eligible for Study:

18 Years to 64 Years (Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

To be eligible, the following inclusion criteria must be met:

Clinical diagnosis of either type 1 diabetes receiving daily insulin since the time of diagnosis for at least 2 years or type 2 diabetes receiving multiple daily insulin doses for at least 2 years.

At least 18.0 years of age and less than 65.0 years.

Body mass index (BMI) greater than or equal to 20.0 and below or equal to 35.0 kg/m2

Weighs at least 50 kg (110 lbs)

Females must meet one of the following criteria:

Of childbearing potential but agrees to use an accepted contraceptive regimen as described in the study procedure manual throughout the entire duration of the study (from the screening visit until study completion).

or

Of non-childbearing potential, defined as a female who has had a hysterectomy or tubal ligation, is clinically considered infertile or is in a menopausal state (at least 1 year without menses).

In good general health with no conditions that could influence the outcome of the trial, and in the judgment of the Investigator is a good candidate for the study based on review of available medical history, physical examination and clinical laboratory evaluations.

Willingness to adhere to the protocol requirements

Exclusion Criteria:

An individual is not eligible if any of the following exclusion criteria are present:

Females who are pregnant according to a positive urine pregnancy test, actively attempting to get pregnant, or are lactating.

History of hypersensitivity to glucagon or any related products or severe hypersensitivity reactions (such as angioedema) to any drugs.

Presence of cardiovascular, gastrointestinal, liver or kidney disease, or any other conditions which in the judgment of the investigator could interfere with the absorption, distribution, metabolism or excretion of drugs or could potentiate or predispose to undesired effects.

History of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma.

History of an episode of severe hypoglycemia (as defined by an episode that required third party assistance for treatment) in the 1 month prior to enrolling in the study.

Use of daily systemic beta-blocker, indomethacin, warfarin or anticholinergic drugs.

History of epilepsy or seizure disorder.

Regularly consumes 3 or more alcoholic beverages per day.

Use of an Investigational Product in another clinical trial within the past 30 days

Donated 225 mL or more of blood in the previous 8 weeks before the first glucagon dosing visit.